The combination of cocaine abuse and HIV infection is an emerging problem and unique challenge for clinicians and researchers. Both are associated with cardiovascular complications alone, including acute events (angina, arrhythmias, myocardial infarction) and chronic conditions (myocarditis, vasculopathy, cardiomyopathy, congestive heart failure), but the mechanisms involved are undefined and and therapeutic strategies have not been optimized. Since they often coexist, it is reasonable to evaluate the pathophysiologic consequences of their combination. In this proposal our primary objectives are to define the mechanisms of cocaine induced cardiovascular dysfunction, and to determine the interactions of cocaine during retroviral infection, using an established and relevant animal model (murine AIDS, LPBM5 infection). Our collaborative studies are designed to provide new and integrated information at the functional, biochemical, cellular, and molecular levels. Our SPECIFIC AIMS are: 1. Test the hypothesis that dysregulation of NO is a key mechanism of cocaine-induced cardiovascular toxicity. -In vivo echocardiography and isolated vascular function will be related to tissue lipid peroxidation, protein nitration, NOS isoforms, and antioxidant enzymes. Transgenic mice will be employed. 2. Define cardiac responses to cocaine induced injury. -Tissue responses to injury will be evaluated, including immune cell infiltration, morphology, and apoptosis. Isolated myocyte electrophysiology, contractile protein function, and myosin isoform expression will also be examined. 3. Test the hypothesis that cardiac and vascular dysfunction is enhanced following cocaine and murine AIDS in combination. -Cardiovascular function, cellular, biochemical, and molecular parameters will be evaluated. 4. Corroborate the findings from our mouse studies using human autopsy tissues. -Cardiac specimens from HIV/AIDS patients will be examined. These studies will yield new information regarding mechanisms of cocaine- and retrovirus-induced complications and provide important insights regarding immune and cardiovascular system interactions.